rs2303995
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The ENST00000388996.10(KCNQ3):āc.1241A>Gā(p.Glu414Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,190 control chromosomes in the GnomAD database, including 1,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.025 ( 134 hom., cov: 33)
Exomes š: 0.027 ( 1213 hom. )
Consequence
KCNQ3
ENST00000388996.10 missense
ENST00000388996.10 missense
Scores
6
11
Clinical Significance
Conservation
PhyloP100: 3.49
Genes affected
KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0017500818).
BP6
Variant 8-132163489-T-C is Benign according to our data. Variant chr8-132163489-T-C is described in ClinVar as [Benign]. Clinvar id is 21409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132163489-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ3 | NM_004519.4 | c.1241A>G | p.Glu414Gly | missense_variant | 9/15 | ENST00000388996.10 | NP_004510.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ3 | ENST00000388996.10 | c.1241A>G | p.Glu414Gly | missense_variant | 9/15 | 1 | NM_004519.4 | ENSP00000373648 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0247 AC: 3752AN: 152188Hom.: 136 Cov.: 33
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GnomAD3 exomes AF: 0.0354 AC: 8886AN: 251066Hom.: 359 AF XY: 0.0338 AC XY: 4588AN XY: 135682
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GnomAD4 exome AF: 0.0273 AC: 39844AN: 1458882Hom.: 1213 Cov.: 29 AF XY: 0.0270 AC XY: 19573AN XY: 726072
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GnomAD4 genome AF: 0.0246 AC: 3747AN: 152308Hom.: 134 Cov.: 33 AF XY: 0.0267 AC XY: 1985AN XY: 74482
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ESP6500AA
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ClinVar
Significance: Benign
Submissions summary: Benign:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Seizures, benign familial neonatal, 2 Benign:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 15, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign Neonatal Epilepsy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign neonatal seizures Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
P;P;P
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Uncertain
Sift
Benign
D;.;D;D;.
Sift4G
Benign
T;T;T;T;.
Polyphen
B;.;.;B;.
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at